Bladder Cancer Patients Research Articles

Impact of declining renal function on bladder cancer (BC) mortality in the U.S. (1999-2023): A regression analysis using the CDC WONDER database.

e16619 Background: BC is associated with significant renal-related mortality. This is attributed to chemotherapy, acute kidney injury (AKI), chronic kidney disease (CKD) with possible dialysis. Older adults are particularly vulnerable due to age-related declines in renal function, comorbidities, and higher prevalence rates. We aimed to evaluate renal-related events as a cause of death in bladder cancer patients, with a focus on demographic trends and the preferred place of death (PPOD) in the U.S. Methods: A nationwide U.S. healthcare database, CDC WONDER, was utilized to assess mortality trends in patients over > 65. Mortality data were categorized using the ICD-10 codes: C67 for bladder cancer, N17-N19 for renal failure, R94.4 for abnormal kidney function studies, and Y84.1 for kidney dialysis. Joinpoint 5.0 software was used for regression analysis to evaluate mortality trends. Data were stratified by demographic factors, including census region, race, sex, and PPOD. Results: The overall trends indicated a significant increase in renal-related mortality from 1999 to 2012 (APC 1.4812, p = 0.000076), followed by an insignificant decline from 2012 to 2015, and a significant increase from 2015 to 2023 (APC 3.1013, p = 0.000078). On census stratification, significantly increased mortality was noted Midwest (1999-2023: APC 0.5492, p = 0.01) and the West (1999-2005: APC 5.0920, p = 0.001809; 2015-2023: APC 2.8382, p = 0.00399). The South also showed significant increasing trends from 1999 to 2018, with an exponential surge from 2018 to 2023 (APC 5.6142, p = 0.005395). By race, notable increases were observed in the Asian population (1999-2023: APC 3.8522, p = 0.000027) and the White population (1999-2012: APC 1.6140, p = 0.0003; 2015-2023: APC 2.878, p = 0.00017). For sex stratification, males showed significant mortality increases, with trends from 1999 to 2012 (APC 2.0621, p = 0.000005) and from 2015 to 2023 (APC 3.2988, p = 0.000111). Regarding PPOD, deaths in hospice, nursing homes, and home settings showed increasing trends from 1999 to 2023 (APC 2.4073, p < 0.000001), while mortality in medical facilities declined from 1999 to 2020 (APC -1.89, p < 0.000001), followed by an exponential surge from 2020 to 2023 (APC 14.5803, p = 0.007). Conclusions: Our study reveals a concerning rise in renal-related mortality among bladder cancer patients who are older adults, males, and Asians. We also highlighted the geographic trends with the midwest, west, and south being the most affected regions. Evolving PPOD patterns suggest increased hospice use, which suggests improved access to end-of-life care. Our findings reveal a potential intervention group within BC patients that can benefit from multi-disciplinary care with nephrology. Further research is needed to uncover the factors driving these trends.

The paradoxical impact of depression on mortality, length of stay, and hospitalization charges in patients with prostate and bladder cancer: Using the 2021 NIS database.

e17148 Background: Depression is a prevalent comorbidity in patients with cancer, potentially influencing treatment outcomes. This study evaluates the association of depression with mortality, length of stay (LOS), and hospitalisation charges (TOTCHG) among patients with prostate cancer and bladder cancer. Methods: We conducted a retrospective analysis of the NIS 2021 database. Hospitalised patients with prostate cancer, bladder cancer and depression were identified using the appropriate ICD-10 codes. Survey-weighted descriptive statistics were utilized to analyze patient demographics, mortality rates, LOS, and TOTCHG. Multivariable logistic and linear regression models evaluated the impact of depression on outcomes, adjusting for age, sex, race, income quartiles, Charlson comorbidity index, hospital region, teaching status, and bed size. Results: In this study, 182,280 hospitalised prostate cancer patients and 40,855 hospitalised bladder cancer patients were analyzed. Among prostate cancer patients, 9.3% (16,785 patients) were depressed, with depressed individuals slightly younger (adjusted coefficient -0.42 years, p=0.036), predominantly White (76.2%, p<0.001), privately insured (76.1%, p<0.001), with higher comorbidity (85.9%, p<0.001), & in the Midwest region (25.9%, p<0.001). Among bladder cancer patients, 11.4% (4,645 patients) were depressed, with depression more common in younger individuals (adjusted coefficient -1.07 years, p=0.004), women (31.4%, p<0.001), White patients (86.9%, p<0.001), those with higher comorbidity (85.8%, p<0.001), Northeast (29.1%, p=0.019) and privately insured (63.2%). Depressed prostate cancer patients had lower mortality rates (3.75% vs. 4.67%, adjusted OR 0.76, p=0.004), shorter hospital stays (5.33 vs 6.13 days, adjusted - 0.72 days, p<0.001), & lower hospitalization charges ($73,977 vs. $85,966, adjusted reduction -$11,699, p<0.001). Depressed bladder cancer patients had lower mortality rates (6.45% vs. 9.53%, adjusted OR 0.63, p=0.001), slightly shorter hospital stays (7.25 vs. 7.66 days, adjusted - 0.42 days, p=0.032), and reduced hospitalization charges ($92,321 vs. $104,156, adjusted reduction -$10,327, p=0.023). Conclusions: This study reveals that depression was more prevalent in younger, White, privately insured patients with higher comorbidities. Interestingly, depressed patients in both cohorts had lower mortality rates, shorter hospital stays, and reduced hospitalisation charges despite their higher comorbidity burdens, suggesting potential differences in healthcare utilisation, disease management, or psychosocial factors. These findings underscore the importance of recognising and addressing depression, as it may not only affect patient quality of life but also play a significant role in shaping clinical and economic outcomes.

Causal Associations Between the Presence of Prostate Cancer or Testosterone Levels and Bladder Cancer Risk: A Mendelian Randomization Study.

Previous observational studies and meta-analyses have indicated that prostate cancer and testosterone levels could be potential risk factors for bladder cancer. However, these studies are vulnerable to confounding variables and reverse causality. Thus, we conducted a 2-sample Mendelian Randomization (MR) study to elucidate the causal link between the presence of prostate cancer or testosterone levels and bladder cancer. We acquired summary statistics for the presence of prostate cancer or testosterone levels and bladder cancer from genome-wide association studies (GWAS). MR analysis was employed to investigate the potential causal relationship between the presence of prostate cancer or testosterone levels and bladder cancer. The primary method employed was the inverse variance weighted (IVW) method, with results rigorously assessed through sensitivity analysis. IVW Mendelian randomization results demonstrated that prostate cancer was causally associated with an elevated risk of bladder cancer in FinnGen (OR 1.22, 95% CI, 1.13-1.31, P < .001), UK Biobank (OR 17.9, 95% CI, 3.28-97.62, P < .001), and the PRACTICAL database (OR 1.13, 95% CI, 1.05-1.22, P < .001). There was no evidence of heterogeneity in the effects of genetic factors on bladder cancer risk, as indicated by Cochran's Q statistical test (FinnGen Q = 68.86, P = .13; UK Biobank Q = 29.05, P = .61; PRACTICAL Q = 108.88, P = .48). Sensitivity analyses confirmed the stability and robustness of the genetically determined risk effect of prostate cancer on bladder cancer. However, there was no causal link between testosterone levels and bladder cancer (P > .05). This study identified that genetically predicted prostate cancer was causally linked to an increased risk of bladder cancer. Appropriate measures should be taken to prevent the subsequent development of bladder cancer in patients with prostate cancer.

Effectiveness of the Continuous Care Model on Quality of Life, Sexual Satisfaction and Function in Bladder Cancer Patients Undergoing Tumor Resection Surgery: A Randomized Control Trial.

Effectiveness of the Continuous Care Model on Quality of Life, Sexual Satisfaction and Function in Bladder Cancer Patients Undergoing Tumor Resection Surgery: A Randomized Control Trial.

MRNA-Based Urine Test Performance in High and Very-High Risk Non-Muscle-Invasive Bladder Cancer Patients Undergoing Contextual Endoscopic Follow-up (VERNAL: Vesical Tumor Early Monitoring: mRNA-Based Follow-up).

mRNA-Based Urine Test Performance in High and Very-High Risk Non-Muscle-Invasive Bladder Cancer Patients Undergoing Contextual Endoscopic Follow-up (VERNAL: Vesical Tumor Early Monitoring: mRNA-Based Follow-up).

Lactylation-mediated IGF2BPs/rmrp axis and effects on bladder cancer progression through the regulation of cancer cells and cancer-associated fibroblasts.

e16576 Background: Bladder cancer (BCa) is a common malignancy with high incidence and mortality. Epigenetic modifications, particularly N6-methyladenosine (m6A) RNA, are critical in BCa progression. IGF2BPs, as m6A readers, stabilize target RNAs and regulate glycolysis, promoting BCa malignancy. Methods: Single-cell sequencing identified elevated IGF2BPs expression in BCa epithelial cells. In vitro experiments assessed the effects of IGF2BPs knockdown on BCa cell proliferation, migration, invasion, and organoid growth. Mechanistic studies investigated the IGF2BPs-RMRP-PDHX axis, glycolysis regulation, lactate production, and TME modulation. Urinary exosomal m6A-RMRP was evaluated as a biomarker. Results: IGF2BPs knockdown suppressed BCa cell proliferation, migration, invasion, and organoid growth. Mechanistically, IGF2BPs stabilized m6A-modified RMRP, which inhibited PDHX, suppressed PDH activity, and promoted glycolysis. Lactate and exosomal RMRP secreted by BCa cells enhanced the TME by promoting cGAS lactylation in CAFs and suppressing the cGAS-STING pathway. This established an immunosuppressive TME, further driving BCa progression. Clinically, urinary exosomal m6A-RMRP correlated with tumor stage, grade, and lymph node metastasis, showing superior diagnostic performance compared to NMP22 testing. Combining m6A-RMRP and NMP22 improved sensitivity and specificity. Conclusions: The IGF2BPs-RMRP-PDHX axis drives BCa progression by regulating glycolysis. Lactate and exosomal RMRP modulate the TME and exacerbate malignancy. Urinary exosomal m6A-RMRP is a promising biomarker for BCa diagnosis and prognosis, offering new insights into its molecular mechanisms and clinical management. Correlation between expression of urinary exosomal m6A-RMRP and clinicopathological characteristics in BCa patients. Characteristics Case Urinary exosomal m6A-RMRP Χ 2 P value Low High All cases 150 75 75 Gender Male 117 60(51.28%) 57(48.72%) 0.350 0.554 Female 33 15(45.45%) 18(54.55%) Age (years) ≤65 68 36(52.94%) 32(47.06%) 0.430 0.512 ＞65 82 39(47.56%) 43(52.44%) Tumor size (cm) ≤3 104 53(50.96%) 51(49.04%) 0.125 0.723 ＞3 46 22(47.83%) 24(52.17%) Tumor stage (T) Ta-T1 117 67(57.26%) 50(42.74%) 8.552 0.003 ** T2-T4 33 8(24.24%) 25(75.76%) Lymph node Metastasis Negative 128 70(54.69%) 58(45.31%) 7.670 0.006 ** Positive 22 5(22.73%) 17(77.27%) Grade Low 30 10(33.33%) 20(66.67%) 4.167 0.041 * Middle-High 120 65(54.17%) 55(45.83%) Tumor number Single 111 55(49.55%) 56(50.45%) 0.035 0.852 Multiple 39 20(51.28%) 19(48.72%) Frequency Primary 115 58(50.43%) 57(49.57%) Recurrence 35 17(48.57%) 18(51.43%) 0.037 0.847 NMP22 Negative 83 44(53.01%) 39(46.99%) 0.674 0.412 Positive 67 31(46.27%) 36(53.73%) *P &lt; 0.05, **P &lt; 0.01.

Correlation of circulating tumor DNA (ctDNA) dynamics with clinical response in muscle-invasive bladder cancer (MIBC) patients (pts) undergoing trimodality therapy (TMT).

4602 Background: TMT is a curative treatment option for pts with MIBC. Plasma circulating tumor DNA (ctDNA) is associated with treatment response and clinical outcomes following cystectomy for MIBC, but the association of plasma ctDNA with treatment response and clinical outcomes in pts treated with TMT is poorly understood. We hypothesize that ctDNA dynamics are correlated with clinical outcomes in pts with MIBC treated with TMT. Methods: Pts with MIBC who received TMT at Dana-Farber/Brigham and Women’s Cancer Center or Massachusetts General Hospital, consented to a research protocol, and underwent ctDNA evaluation with the commercially available Signatera assay were included in the analysis. Individual chart review was performed to collect demographic and clinical data. Results: A total of 67 pts had at least one ctDNA evaluation and were included in this analysis. Cohort characteristics are summarized in Table 1. Forty-eight pts had at least one ctDNA evaluation prior to TMT, and 17 (35%) were ctDNA(+). Of the pts who were ctDNA(+) prior to TMT, 12 had at least one post-TMT ctDNA evaluation and 7 of 12 (58%) converted to ctDNA(-). Thirty-one pts were ctDNA(-) prior to TMT: 24 (77%) have had ≥1 post-TMT ctDNA evaluation and all 24 remained ctDNA(-) at the first post-TMT evaluation (median 8 weeks after TMT completion). Of the 55 pts with ≥1 post-TMT ctDNA result, 46 (84%) have remained ctDNA(-) during subsequent follow-up and do not have clinical evidence of recurrence (median number of ctDNA evaluation, 2; median follow up, 44 weeks). Nine pts had a ctDNA(+) result in the post-TMT setting: 5 were also ctDNA(+) prior to TMT, 2 did not have a pre-TMT ctDNA assessment but were ctDNA(+) at first-post TMT assessment, and 2 were ctDNA(-) before and initially after TMT but subsequently converted to ctDNA(+). Of these 9 ctDNA(+) cases, 6 pts (67%) have developed clinical evidence of metastatic disease to date with a median lead time of 5.3 weeks (range, 0-27 weeks) between first ctDNA(+) assessment and clinical evidence of metastatic disease. Overall, the sensitivity of plasma ctDNA testing in the post-TMT setting was 100% and the specificity was 94%. Conclusions: Most pts with MIBC treated with TMT in this cohort were ctDNA(-) following TMT and did not develop evidence of recurrent invasive or metastatic disease. Pts with ctDNA(+) status in the post-TMT setting frequently developed clinical evidence of metastatic disease. Larger cohorts with longer follow-up will be required to determine whether ctDNA status may be useful in guiding clinical decisions in MIBC pts undergoing TMT. No. of Pts 67 Median Age (Yrs) 75 M:F 59:8 T3-4 (%) 16 (24%) ≥N1 (%) 3 (4%) Presence of variant histology (%) 13 (19%) Received neoadjuvant chemotherapy (%) 12 (18%) Received concurrent chemotherapy (%) 61 (91%) Median RT dose (Gy) 55 Median length of follow up (weeks) 39

Comparative analysis of the anti-tumor activity and mechanism of action of TARA-002 and BCG in bladder cancer models.

e16613 Background: Intravesical instillations of Bacillus Calmette-Guérin (BCG) is the current standard of care for high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) patients. TARA-002, a preparation of inactivated Streptococcus pyogenes, is currently in a Phase-2 (ADVANCED-2) clinical trial for the treatment of NMIBC. Interim analysis found that the rates of high-grade complete response (CR) at month 6 were 72% overall, 64% in BCG-naïve subjects and 100% in BCG-unresponsive patients with TARA-002 treatment. As TARA-002 and BCG are regarded as broad immunopotentiators, we compared the anti-tumor activity and mechanisms of action of TARA-002 and BCG using bladder cancer models. Methods: TARA-002 internalization in HEK293 Wild Type (WT) and TLR2 Knockout (KO) and Bladder Cancer (BC) cells (RT112 and T24) was evaluated by confocal microscopy. Flow Cytometry analysis of Annexin V, marker of apoptosis, was used to evaluate TARA-002 and BCG cytotoxicity in mouse and rat BC cells (MBT2, MB49 and AY27) after 24 h treatment. Cytokine analysis was conducted on 5637 BC cells co-cultured with peripheral blood mononuclear cells (PBMCs) following treatment with either BCG or TARA-002 for 24 h. Lastly, the MB49 orthotopic bladder cancer mouse model evaluated tumor growth inhibition and survival upon TARA-002 intravesical treatment. Results: Unlike BCG, which relies on fibronectin receptors for internalization, TARA-002 internalization was unaffected by fibronectin receptor blockade and was instead shown to be TLR2-dependent as the HEK293 TLR2-KO cells consistently displayed lower levels of intracellular TARA-002 compared to the WT counterpart. Furthermore, TARA-002 exhibited significant dose-dependent cytotoxicity against BC cell lines, while BCG showed only modest tumor-killing effects. Co-culture of 5637 BC cells and PBMCs showed that TARA-002 treatment increased pro-inflammatory Th1 cytokines (TNF-a, IFN-g, IL-12p70) and reduced IL-8 levels, a marker linked to poor BC prognosis, compared to BCG. Finally, intravesical instillations of TARA-002 in the BCG-unresponsive MB49 orthotopic model showed a strong anti-tumor effect and significantly enhanced survival outcomes. Since BCG exposure induces trained immunity, it is plausible that BCG-induced trained immunity may enhance the response to TARA-002, potentially explaining its improved efficacy in BCG-treated patients compared to the BCG-naïve population. To evaluate this hypothesis, preclinical tests are being conducted at the time of submission. Conclusions: Our results suggest that the mechanism of action of TARA-002 differs from that of BCG, leading to variations in their biological activity. This leads to more potent anti-tumor activity of TARA-002 in both in vitro and in vivo models compared to BCG, accompanied by an enhanced immune-mediated pro-inflammatory response.

Safety of angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) in patients with bladder and upper tract malignancies undergoing platinum-based chemotherapy: A retrospective study.

e16563 Background: ACEis and ARBs are commonly used in the management of hypertension and cardiovascular disease, but little is known about their safety and impact on renal clearance when used in patients with bladder and upper tract malignancies receiving platinum-based chemotherapy (PBC). Methods: We performed an IRB-approved retrospective analysis of patients with bladder and upper tract malignancies at the University of California, Irvine, who received PBC between November 2017 and July 2023. Patients were grouped into cohort 1 (PBC + ACEis/ARBs) and cohort 2 (PBC without ACEis/ARBs). We used Chi-square tests for categorical variables and Student’s t-tests for continuous variables, with logistic regression to identify independent risk factors. Results: A total of 145 patients (mean age: 70) were included, with 47/145 (32%) receiving ACEis/ARBs at chemotherapy initiation. 64/145 (44%) were treated for metastatic disease and 11/145 (7.6%) received chemoradiation. Cisplatin was given to 84/145 (57.9%), carboplatin to 58/145 (40%). While chemotherapy regimen modifications (dose reductions, delays, cessations) were more frequent in cohort 1, the difference was not statistically significant (66% vs. 51%, P = 0.09). Independent risk factors associated with any regimen alterations included older age (in years) (aOR, 1.06; 95% CI, 1.02 to 1.10; P = 0.001) and receipt of carboplatin (aOR, 2.11; 95% CI, 1.01 to 4.40; P = 0.046). Chemotherapy-induced cytopenia was found in 32/47 (68.1%) of patients in cohort 1 vs. (56/98) 57.1% of patients in cohort 2, P = 0.21). No significant differences in acute kidney injury (P = 0.57) or hospitalization rates (P = 0.18) were observed. In multivariable logistic regression analysis, older age (aOR, 1.09; 95% CI, 1.05 to 1.14; P &lt; 0.001) and metastatic disease (aOR, 2.41; 95% CI, 1.08 to 5.35; P = 0.031) were associated with any cytopenia or AKI. Conclusions: Concurrent use of ACEis/ARBs in bladder and upper tract cancer patients receiving PBC was associated with trends toward higher chemotherapy-induced toxicities and treatment alterations, though these findings were not statistically significant. Older age and metastatic disease were associated with cytopenias or AKI. These trends are worth exploring further in larger studies to ensure patient safety and treatment efficacy.

First-in-human study of RAG-01: A novel small activating RNA therapeutic in BCG failure non-muscle invasive bladder cancer (NMIBC) patients.

e16587 Background: Targeting the p21 WAF1/CIP1 (p21) gene represents a promising yet challenging therapeutic strategy in cancer treatment. p21, a critical cell cycle inhibitor with significant tumor suppressive potential, has remained largely "undruggable" for conventional modalities. RAG-01 introduces a novel approach using small activating RNA (saRNA) technology to directly upregulate p21 gene expression at the transcriptional level via the RNAa mechanism. This study (NCT06351904) represents the first-in-human clinical trial of a saRNA targeting p21, in patients with NMIBC to establish a potential novel therapeutic paradigm in the treatment of cancer by activating tumor suppressor genes. Methods: This open-label, multi-center, phase I study uses a 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of intravesical RAG-01 in patients with Bacillus Calmette Guérin (BCG) unresponsive NMIBC. Patients receive RAG-01 at escalating doses (30 mg, 100 mg, 300mg, and 600 mg). Two doses will be selected for the expansion phase. Treatment consists of a 6-week induction course (weekly instillations) followed by maintenance of 3 weekly instillations every 12 weeks (weeks 12, 24, 36, 48, and 72). Patients with persistent carcinoma in situ (CIS) or high-grade Ta at 12 weeks may receive a six-week re-induction. Results: As of December 15, 2024, 9 patients were enrolled across 3 dose-escalation cohorts (30-300 mg). Dose escalation is ongoing, and no dose-limiting toxicities (DLTs) have occurred. Adverse events (AEs), all grade ≤2, were reported in 8 patients (88.9%, 8/9). The most frequently reported AEs included urinary urgency (11.1%, 1/9), increased urinary frequency (11.1%), urinary tract infection (11.1%), dyspnea (11.1%), lethargy (11.1%), nausea (11.1%), and decreased appetite (11.1%). RAG-01 showed minimal systemic exposure with a dose-dependent maximum urine concentration (83.3-1,820 µg/ml at 2 hours) and urine AUC 0-24h . A dose-dependent increase in p21-positive urothelial cells was observed. Preliminary efficacy analysis revealed a 66.7% (2/3) complete response rate for CIS at any time and a 66.7% (2/3) disease-free survival rate for papillary tumors at 3 months. Conclusions: Intravesical RAG-01 demonstrated a favorable safety profile across three escalating dose levels (30, 100, and 300 mg). Dose-dependent p21 protein induction in urothelial cells confirmed target engagement. Preliminary anti-tumor efficacy supports further clinical investigation of this saRNA as a novel therapeutic approach for NMIBC. Clinical trial information: NCT06351904 .

Association between drinking water disinfection byproducts exposure and human bladder cancer: A time-updated meta-analysis of trihalomethanes.

Association between drinking water disinfection byproducts exposure and human bladder cancer: A time-updated meta-analysis of trihalomethanes.

An exploratory study of clostridium butyricum combined with neoadjuvant chemoimmunotherapy in urothelial carcinoma.

4585 Background: Neoadjuvant chemoimmunotherapy using gemcitabine, cisplatin, and anti-PD1 has shown survival benefits for advanced bladder cancer patients, though response rates remain low. Recent studies highlight the role of clostridium butyricum in anti-tumor immunity, but its potential to enhance bladder cancer therapy is unexplored. Methods: This exploratory study (NCT06696742) involved patients with cT2-T4aN0M0 urothelial carcinoma at First Affiliated Hospital of Nanjing Medical University. Participants were randomized into two groups, one received with GC+anti-PD1 (gemcitabine 1.0 g/m 2 D1 and D8, cisplatin 70 mg/m 2 D2-4, and tislelizumab 200 mg D8 once every 21 days for 3-4 cycles), and the other received the same regimen plus Clostridium butyricum tablets (1-2 tablets, three times a day). Primary observations were pathological complete response (pCR, ypT0) and pathological down-staging ( &lt; ypT2), the second observations included imaging assessment (RECIST 1.1) and safety. Results: In the combination group, 23 out of 30 patients completed treatment and underwent radical cystectomy, achieving a clinical complete response (CR) rate of 52.2% (12/23) and a partial response (PR) rate of 39.1% (9/23). Two patients (8.6%) showed stable disease (SD) and seven patients are still receiving treatment. Pathological downstaging was observed in 82.6% (19/23) of the patients, with 52.2% reaching ypT0 (12/23). In the control group, all 26 enrolled patients completed treatment and underwent radical cystectomy. The clinical CR rate was 30.7% (8/26), while the clinical PR rate was 42.3% (11/26). Six patients (23.1%) had stable disease, and 1 patient (3.8%) experienced disease progression (PD). Pathological downstaging occurred in 61.5% (16/26) of the patients, with 26.9% (7/26) achieving ypT0. The combination group demonstrated significantly higher rates of clinical CR+PR (P = 0.037) and pathological downstaging (P = 0.042) compared to the control group. There was no statistical difference between the two groups in terms of demographic characteristics. Conclusions: Combining neoadjuvant chemoimmunotherapy with Clostridium butyricum improves pathological and clinical response rates in cT2-T4aN0M0 urothelial carcinoma patients. Clinical trial information: NCT06696742 .

Multicenter Retrospective Registry Study on BCG Use in Non-Muscle Invasive Bladder Cancer in Latin America: BLATAM (Bladder Cancer in Latin America) Group.

This study, conducted by the Bladder Cancer in Latin America (BLATAM) group, aims to analyze epidemiological and therapeutic data on non-muscle invasive bladder cancer (NMIBC) in Latin American patients. It seeks to identify factors contributing to suboptimal responses to Bacillus Calmette-Guérin (BCG) therapy and assess areas for improvement in regional treatment practices. A multicenter retrospective study was carried out in collaboration with reference Urology Departments across Latin America. Data were collected using an electronic Case Report Form (CRF) from 2011 to 2021, capturing demographics, clinical presentation, treatment details, and follow-up of NMIBC patients treated with BCG. Statistical analyses included Kaplan-Meier survival analysis for relapse-free survival (RFS). Data from 292 patients across five countries were analyzed, with a mean age of 70.3 years and a male prevalence of 74%. Smoking history was reported in 70.6% of patients. The mean time to the first BCG dose was 2.4 months post-TURBT, with 26.7% of patients exceeding the recommended 60-day window for induction initiation. While 84% of patients completed BCG induction, only 45.9% followed the recommended Lamm maintenance schedule. Delays in starting maintenance cycles were observed, with a median delay of over 36 days for the first cycle and 65 days for the second cycle. RFS at 1 year and 5 years for high-risk patients was 87.3% and 53.3%, respectively. This study highlights critical deviations from recommended NMIBC management protocols in Latin America, including delayed BCG initiation and inconsistencies in maintenance therapy. These findings emphasize the need for standardized treatment protocols and improved adherence to international guidelines, which could enhance NMIBC patient outcomes in the region. Collaborative efforts are essential to develop region-specific strategies, improve data collection, and ultimately provide better care for bladder cancer patients in Latin America.

Quantum mechanics–based multi-tensor AI/ML discovery and validation of actionable and mechanistically interpretable whole-transcriptome predictors of survival in response to immunotherapy from real-world clinical trial data.

2621 Background: Prediction in cancer remains limited, and 90% of drugs continue to fail trials and post-market validation. The entire multi-ome affects the disease. Previously, we developed quantum mechanics-based multi-tensor AI/ML to overcome the limitations of typical AI/ML, e.g., neural networks and deep learning, in small-cohort, noisy, high-dimensional, multi-omic clinical data [doi: 10.1073/pnas.0530258100 , 10.1145/3624062.3624078 ]. We have demonstrated the algorithms in the discovery and validation of whole-genome and -chromosome predictors of survival and response to treatment in, e.g., brain, lung, ovarian, and uterine cancers [doi: 10.1063/1.5142559 , 10.1200/JCO.2024.42.16_suppl.10043 ]. Methods: Here, we use the algorithms to discover two whole-transcriptome predictors of OS in response to atezolizumab PD-L1 inhibitor immunotherapy in a 348-patient, multi-center, single-arm, bladder cancer clinical trial, and validate the predictors in the 401-patient bladder cancer cohort in the Cancer Genome Atlas (TCGA). Results: The algorithms discovered the two predictors in the open-source, pre-atezolizumab, locally advanced or metastatic disease profiles of the 348 patients alone. By incorporating the patient labels, both predictors were found to outperform the best indicator of response to the treatment to date, i.e., the tumor mutation burden (TMB): The Cox proportional hazards model ratios, i.e., the corresponding relative risks, of 2.7 and 1.7, and concordance indices, i.e., accuracies, of 0.70 and 0.63, of each predictor, are greater than the ratio, of 1.3, and index, of 0.61, of TMB (Wald P -values=2.0×10 -7 and 8.2×10 -3 vs. 2.1×10 -5 ). The maximum Kaplan-Meier median OS difference of the two predictors together, of 22 months, is greater than that of TMB, of 16 months (log-rank P -values=3.6×10 -11 vs. 1.7×10 -4 ). One predictor is additionally correlated with the objective response rate (ORR), and the other – with the tissue of advanced or metastatic disease (Kruskal-Wallis P -values=9.8×10 -4 and 2.2×10 -3 ). Both predictors are similarly correlated with the OS of the 401 TCGA bladder cancer patients. Both are statistically independent of the imbalanced variations in the patient demographics, e.g., race, or the tissue batches, e.g., pre- vs. post platinum-based chemotherapy. By using the transcript labels, the predictors were interpreted in terms of known and new disease mechanisms and drug targets to sensitize the tumors to the treatment. Conclusions: Our multi-tensor AI/ML discovered and validated two whole-transcriptome predictors of OS in response to atezolizumab that outperform TMB. This further suggests that quantum mechanics-based algorithms can be used to derive predictors that are consistent across studies and over time.

ABLE-41, a real-world evidence study for bladder cancer patients treated with nadofaragene firadenovec: Baseline patient characteristics and demographics.

e16608 Background: Nadofaragene firadenovec-vncg is the first FDA-approved intravesical nonreplicating adenoviral vector-based gene therapy which delivers interferon alpha 2b into the bladder urothelial cells for treatment of high-risk Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) ± papillary tumors. “ADSTILADRIN in BLadder cancEr” (ABLE)-41 (NCT06026332) is a phase 4 multicenter non-interventional study examining nadofaragene utilization and outcomes in the real-world setting. While the primary outcome is complete response rate, secondary outcomes include patterns of use as well as patient, caregiver and prescribing physician experience which can provide key insights beyond registrational trials. In this study we present our baseline demographic findings for the initial cohort of patients. Methods: Adult patients receiving nadofaragene firadenovec-vncg in routine clinical practice were offered enrollment following informed consent to share data. The study included optional surveys for patient and caregiver experience. Results: As of October 2024, 54 patients have been enrolled from 17 US centers. Median age was 79 years (range 50-92, IQR 73-85) which is higher than our Phase 3 trial (71 years IQR 66-77). Patients were mostly male (87.0%) and White (96.3%). While 97.4% were ECOG ≤2 one patient had an ECOG status of 3 (excluded in the phase 3 trial). For the 47 patients with complete pathology data at first dose, 30 (65.2%) had CIS ± papillary tumors, and 5 (10.6%) were CIS only. 17 (36.1%) had papillary tumors only which included 3 low grade tumors and one T2 tumor. Of 47 patients with documented BCG unresponsive disease, 34 (72.3%) were BCG refractory and 13 (27.1%) were BCG relapsed. Interestingly, 2 patients had received prior radiotherapy for their NMIBC. For 32 patients who chose to fill out the baseline survey, 27 (50%) had no or slight concerns about side effects, 24 (75%) had no issues with activities of daily living, 31 (96.9%) had no or slight anxiety or depression and 27 (84.4%) had no or slight pain. Conclusions: Early data from the real-world usage of nadofaragene firadenovec in this study demonstrates patients are older than those in the phase 3 trial but despite having 1 subject with ECOG status &gt; 2, they self-report low levels of pain and limitations on daily living activities. Inclusion of patients outside the FDA label and clinical guidelines may provide unique insights and hypothesis generation. Clinical trial information: NCT06026332 .

SIRI as a biomarker for bladder neoplasm: Utilizing decision curve analysis to evaluate clinical net benefit.

SIRI as a biomarker for bladder neoplasm: Utilizing decision curve analysis to evaluate clinical net benefit.

The potential of disitamab vedotin in bladder preservation during neoadjuvant therapy for bladder cancer: A comparative analysis with the GC regimen.

e16585 Background: The goal of neoadjuvant therapy for bladder cancer is to improve pathological outcomes and provide patients with the opportunity to preserve the bladder. Disitamab Vedotin, a HER2-targeted antibody-drug conjugate (ADC), has shown significant efficacy in metastatic urothelial carcinoma. This study aims to evaluate the potential of Disitamab Vedotin in promoting bladder preservation during neoadjuvant therapy for bladder cancer. Methods: A retrospective analysis of clinical data from 44 bladder cancer patients was conducted. Patients were divided into two groups: Group A (Disitamab Vedotin monotherapy or combined with immunotherapy, n = 21) and Group B (GC regimen, n = 23). The primary endpoints included complete response (CR) rate, bladder preservation rate, and adverse events. Results: The CR rate in Group A was significantly higher than in Group B (76.2% vs. 39.1%, P = 0.017). The bladder preservation rate was also higher in Group A (66.7% vs. 34.8%, P = 0.069). Group A had a lower incidence of hematologic toxicities, including leukopenia (38.1% vs. 73.9%, P = 0.032) and neutropenia (19.0% vs. 52.2%, P = 0.031). Other adverse events, such as hepatotoxicity and peripheral neuropathy, showed no significant differences between the two groups. Severe adverse events (Grade 3–4) were rare, indicating good tolerability for both regimens. Conclusions: The Disitamab Vedotin regimen demonstrated better efficacy and safety compared to the GC regimen in neoadjuvant therapy for bladder cancer. Its higher CR rate and potential for bladder preservation make it a promising option for organ-sparing treatment. However, given the small sample size and the retrospective nature of this study, further validation through large-scale, multicenter prospective studies is required.

TNF-α drives bladder cancer metastasis via METTL3-mediated m6A modification to promote CLASP2/IQGAP1-dependent cytoskeleton remodeling.

TNF-α drives bladder cancer metastasis via METTL3-mediated m6A modification to promote CLASP2/IQGAP1-dependent cytoskeleton remodeling.

Neutrophil extracellular traps and reactive oxygen species: Predictors of prognosis in bladder cancer.

Neutrophil extracellular traps and reactive oxygen species: Predictors of prognosis in bladder cancer.

Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden: A Real-World Observational Study From the French National Healthcare System Database.

Incidence of Bladder Cancer, Healthcare Pathways, and Economic Burden: A Real-World Observational Study From the French National Healthcare System Database.